The National Institutes of Child Health and Human Development awarded Phase I and Phase II Small Business Innovative Research Grants to develop The Visible Embryo. Initally designed to evaluate the internet as a teaching tool for first year medical students, The Visible Embryo is linked to over 600 educational institutions and is viewed by more than one million visitors each month.

Today, The Visible Embryo is linked to over 600 educational institutions and is viewed by more than 1 million visitors each month. The field of early embryology has grown to include the identification of the stem cell as not only critical to organogenesis in the embryo, but equally critical to organ function and repair in the adult human. The identification and understanding of genetic malfunction, inflammatory responses, and the progression in chronic disease, begins with a grounding in primary cellular and systemic functions manifested in the study of the early embryo.

The World Health Organization (WHO) has created a new Web site to help researchers, doctors and
patients obtain reliable information on high-quality clinical trials. Now you can go to one website and search all registers to identify clinical trial research underway around the world!

Disclaimer: The Visible Embryo web site is provided for your general information only. The information contained on this site should not be treated as a substitute for medical, legal or other professional advice. Neither is The Visible Embryo responsible or liable for the contents of any websites of third parties which are listed on this site.

Premature infants can need special medical care in a
neonatal intensive
care unit. Preterm birth causes more than
1 million deaths a year
and can
leave premature
infants who survive with lifelong medical challenges
ranging from respiratory distress to developmental problems.

According
to the US Centers for Disease Control, nearly 500,000 babies
are every
year prematurely, or before the completion of 37 weeks of pregnancy. Because premature infants are born too early, they weigh less than full-term babies and may have health problems because their organs did not have enough time to develop.

Preterm birth causes more than 1 million deaths a year and can leave premature infants who survive with lifelong medical challenges ranging from respiratory distress to developmental problems. In new findings, scientists provide important new insights into this major global health problem—one that remains stubbornly persistent in the United States.

New research published in the Journal of Clinical Investigation provides evidence that gene-environment interactions are a major contributor to preterm birth and that using a combinatory treatment strategy can prevent preterm delivery in a mouse model.

The study was led by Sudhansu K. Dey, PhD, director of Reproductive Sciences at Cincinnati Children’s, first author Jeeyeon Cha, an MD/PhD graduate student in the Dey lab, and Yasushi Hirota, MD/PhD, a former postdoctoral fellow in the Dey lab and faculty member at the Department of Obstetrics & Gynecology in the Graduate School of Medicine at the University of Tokyo.

The combined impact of genetic predisposition and environmental stress on preterm birth has received increased attention by researchers to determine its causes and potential preventive strategies. Scientists in the current study tested gene-environment interactions in a robust mouse model of prematurity and identified a similar molecular signature in human tissue samples from women who experienced premature birth.

Dey: “Although gene-environment interactions are assumed to be major contributors to preterm birth, this concept had not been experimentally interrogated. Our studies in mice provide evidence that when a genetic predisposition is combined with mild inflammation, the rate of preterm birth is profoundly increased, provoking preterm birth in 100 percent of the females.

“The results are also clinically relevant because aspects of the molecular signatures observed in the mouse studies are consistent with those observed in tissue samples of women who had undergone preterm birth."

A recent report from the World Health Organization states that while more than 60 percent of preterm births occur in developing countries, the U.S. is among ten countries with the highest numbers of preterm birth.

Dey and his colleagues said this suggests that factors behind preterm birth in developing and developed countries may be different.

Infection/inflammation may affect developing countries more, while chronic diseases such as diabetes and hypertension and the increased use of assisted reproductive technologies in older women may increase prematurity rates in developed countries.

To conduct their research, the investigators generated a mouse model of preterm delivery in which the Trp53 gene was conditionally inactivated in the uterus. Trp53 encodes the p53 protein, which is a tumor suppressor and regulates cell growth and replication.

Through a series of studies, the scientists have reported these mice exhibit a preterm birth rate of 50 percent just from the genetic deletion. The scientists have also shown the mice exhibit increased signaling by mammalian target of rapamycin complex 1 (mTORC1) and cyclooxygenase-2 (COX2), which generates fatty acids called prostaglandins that trigger uterine contractions. These pathways are associated with premature senescence of uterine decidual cells, provoking spontaneous early birth.

In the current study, Trp53-deficient females were subjected to mild inflammation with LPS (endotoxin), resulting in a preterm birth rate of 100 percent. They also observed that women who had experienced preterm birth showed similar increases in mTORC1 and COX2 signaling.

The scientists then designed an experimental treatment strategy to prevent preterm birth in Trp53-deficient mice exposed to LPS – a combination of rapamycin (an mTORC1 inhibitor) and progesterone, an ovarian hormone necessary for pregnancy success.

They report the treatment was effective at preventing preterm birth with no apparent adverse effects on maternal or fetal health.

Progesterone is currently in clinical use to prevent preterm birth in select populations of at-risk women. Although further in-depth investigation is required, the scientists suggest that a combined therapy with low doses of an mTORC1 inhibitor and progesterone may help reduce the incidence of preterm birth in high-risk women.

Abstract
There are currently more than 15 million preterm births each year. We propose that gene-environment interaction is a major contributor to preterm birth. To address this experimentally, we generated a mouse model with uterine deletion of Trp53, which exhibits approximately 50% incidence of spontaneous preterm birth due to premature decidual senescence with increased mTORC1 activity and COX2 signaling. Here we provide evidence that this predisposition provoked preterm birth in 100% of females exposed to a mild inflammatory insult with LPS, revealing the high significance of gene-environment interactions in preterm birth. More intriguingly, preterm birth was rescued in LPS-treated Trp53-deficient mice when they were treated with a combination of rapamycin (mTORC1 inhibitor) and progesterone (P4), without adverse effects on maternal or fetal health. These results provide evidence for the cooperative contributions of two sites of action (decidua and ovary) toward preterm birth. Moreover, a similar signature of decidual senescence with increased mTORC1 and COX2 signaling was observed in women undergoing preterm birth. Collectively, our findings show that superimposition of inflammation on genetic predisposition results in high incidence of preterm birth and suggest that combined treatment with low doses of rapamycin and P4 may help reduce the incidence of preterm birth in high-risk women.

Funding for this research was supported in part by the National Institutes of Child Health and Human Development, National Institute on Drug Abuse, National Institute of Aging, (HD12304, DA06668, DA032150) the Bill and Melinda Gates Foundation (Grand Challenges Explorations Initiative), the March of Dimes, Precursory Research for Embryonic Science and Technology (PRESTO, Japan Society for the Promotion of Science), the Takeda Science Foundation, the Kowa Life Science Foundation, and the Yamaguchi Endocrine Research Foundation.

About Cincinnati Children’s
Cincinnati Children’s Hospital Medical Center ranks third in the nation among all Honor Roll hospitals in U.S.News and World Report’s 2013 Best Children’s Hospitals ranking. It is ranked #1 for cancer and in the top 10 for nine of 10 pediatric specialties. Cincinnati Children’s is one of the top two recipients of pediatric research grants from the National Institutes of Health, and a research and teaching affiliate of the University of Cincinnati College of Medicine. The medical center is internationally recognized for improving child health and transforming delivery of care through fully integrated, globally recognized research, education and innovation. Additional information can be found at www.cincinnatichildrens.org. Connect on the Cincinnati Children’s blog, via Facebook and on Twitter.

Original press release:http://www.cincinnatichildrens.org/news/release/2013/premature-birth-08-27-2013/